抗核抗体在类风湿关节炎中的临床研究进展

doi:10.16150/j.1671-2870.2023.06.011

摘要/Abstract

摘要：

类风湿关节炎（rheumatoid arthritis, RA）是一种常见的以侵蚀性关节炎为主要特征的慢性、全身性自身免疫性疾病。全球RA患病率为0.25%~1.00%，其最终可能导致关节畸形和功能丧失。抗核抗体（antinuclear antibody, ANA）指以真核细胞各种成分为靶抗原的自身抗体的总称，在RA患者中的检出率为30%~60%，但在RA诊疗中的应用价值目前尚不明确。RA患者中ANA以低滴度为主，荧光核型以核颗粒型与均质型常见，ANA各种针对靶抗原抗体的检出率通常低于ANA。ANA阳性RA患者类风湿因子、抗环瓜氨酸肽抗体血清水平更高，影像学所见关节侵蚀更显著，因此ANA有望成为预测严重关节损伤的指标。ANA阳性RA患者更易出现关节外表现[如皮下结节（82%比46%）、眼部损害（38%比6%）和感染（38%比12%）]，且更常伴随血管炎、继发干燥综合征，故需关注ANA高滴度患者。在RA合并症方面，相对于ANA阴性组，ANA阳性组中重度贫血（16.04%比6.9%、6.6%比0.07%）、干燥综合征（19.5%比4.1%）、血管炎（29%比7%）高。此外，ANA阳性是老年RA合并颈动脉内膜增厚（HR=4.089）的危险因素，也是女性RA不良妊娠结局（OR=3.268, P=0.045）的独立危险因素。在治疗方面，基线ANA阳性的RA患者对肿瘤坏死因子抑制剂（tumor necrosis factor-α inhibitor, TNFi）治疗反应较差，且基线ANA阳性尤其是高滴度患者更易产生抗药物抗体。药物诱导ANA滴度升高与TNFi继发无应答相关，监测ANA变化有望预测TNFi长期疗效。药物性狼疮是TNFi最常见的不良反应，已证实TNFi诱导抗双链DNA抗体与疗效不佳相关，但仍欠缺大样本研究证实ANA滴度升高或抗双链DNA抗体的产生与药物性狼疮的诱导存在相关性。本文综述RA群体ANA特征、ANA阳性RA临床表现、ANA与TNFi预后关联等方面的研究进展，为ANA作为RA新的生物标志物研究提供参考。

关键词: 类风湿关节炎, 抗核抗体, 肿瘤坏死因子抑制剂

Abstract:

Rheumatoid arthritis (RA) is a common chronic, systemic autoimmune disease characterized by erosive arthritis, with a global prevalence of 0.25% to 1.00%, which may ultimately lead to joint deformity and loss of function. Antinuclear antibody (ANA) refers to auto-antibodies that target various components of eukaryotic cells. Although ANA may be frequently detected in RA patients, with a positive rate of 30% to 60%, the significance of ANA in the diagnosis and treatment of RA remains unclear. Nuclear patterns in RA population are dominated by speckled and homogeneous patterns, mainly at low titres. The detection rate of extractable nuclear antibodies is usually lower than that of ANA. The serum levels of rheumatoid factor and anti-cyclic citrullinated peptide antibody in ANA-positive RA patients are much higher than ANA-negative ones, and joint erosion of ANA-positive RA patients had more severe joint erosion on imaging as well. Therefore, ANA is a potential predictor of severe joint injury. ANA-positive RA patients are more likely to have extra-articular manifestations [such as subcutaneous nodules(82% vs 46%), ocular lesions(38% vs 6%), and infections(38% vs 12%)].In terms of RA comorbidities, compared to the ANA negative group, the ANA positive group had higher levels of moderate and severe anemia (16.04% vs 6.9%; 6.6% vs 0.07%), Sjogren's syndrome (19.5% vs 4.1%), and vasculitis (29% vs 7%). In addition, ANA positivity is an independent risk factor for elderly RA patients with carotid intimal thickening (HR=4.089) and adverse pregnancy outcomes in female RA (OR=3.268, P=0.045), respectively. Attention should be paid to high-titre ANA-positive RA patients for preventive measures. In terms of treatment, RA patients who are ANA-positive when given tumour necrosis factor-α inhibitor (TNFi) treatment got much poorer therapeutic response than ANA-negative ones, especially those with high titres were more prone to generating anti-drug antibodies. Increase of ANA titer induced by TNFi is associated with no response to TNFi treatment, thus monitoring the change of ANA may predict the long-term efficacy of TNFi. The most common adverse event of TNFi is drug-induced lupus. Although it has been confirmed that the induction of anti-double-stranded DNA antibodies is associated with poor efficacy of TNFi, large-scale studies are still needed to confirm the correlation between the increase of ANA titer or ocurence of dsDNA antibody and the induction of drug-induced lupus. In conclusion, this paper reviews the research progress on ANA characteristics in RA population, clinical manifestations of ANA-positive RA, and the association between ANA and TNFi prognosis. The potential of ANA as a new biomarker of RA needs to be further studied.

Key words: Rheumatoid arthritis, Antinuclear antibodies, Tumor necrosis factor-α inhibitor

中图分类号:

郦源, 张乐, 殷翰林, 郑冰, 吕良敬. 抗核抗体在类风湿关节炎中的临床研究进展[J]. 诊断学理论与实践, 2023, 22(06): 579-586.

LI Yuan, ZHANG Le, YIN Hanlin, ZHENG Bing, LÜ Liangjing. Clinical research on progress of antinuclear antibody in rheumatoid arthritis[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(06): 579-586.

参考文献 45

[1]	DI MATTEO A, BATHON J M, EMERY P. Rheumatoid arthritis[J]. Lancet, 2023, 402(10416):2019-2033. doi: 10.1016/S0140-6736(23)01525-8 pmid: 38240831
[2]	FINCKH A, GILBERT B, HODKINSON B, et al. Global epidemiology of rheumatoid arthritis[J]. Nat Rev Rheumatol, 2022, 18(10):591-602. doi: 10.1038/s41584-022-00827-y pmid: 36068354
[3]	VAN-DELFT M A M, HUIZINGA T W J. An overview of autoantibodies in rheumatoid arthritis[J]. J Autoimmun, 2020, 110:102392.
[4]	陈秀慧, 温奕欣, 温天道. 联合检测血清RF、AKA、CRP、抗-CCP抗体、ANA水平在诊断类风湿关节炎中的价值分析[J]. 中国医药科学, 2020, 10(5):168-170,189.
	CHEN X H, WEN Y X, WEN T D. Analysis of combined detection of serum RF, AKA, CRP, anti-CCP and ANA level in diagnosing rheumatoid arthritis[J]. China Med Pharm, 2020, 10(5):168-170,189.
[5]	李建军. 抗核抗体, 抗CCP抗体和RF联合检查对类风湿关节炎诊断价值研究[J]. 临床研究, 2022, 30(2):120-124.
	LI J J. The value of joint inspection of anti-nuclear antibody, anti-CCP antibody and RF in the diagnosis of rheumatoid arthritis[J]. Clin Res, 2022, 30(2):120-124.
[6]	赵婵媛, 闻苗苗. RF、Ig、ANA与抗ENA抗体检测在类风湿关节炎患者诊断及预后分析中的价值[J]. 检验医学与临床, 2021, 18(23): 3408-3411.
	ZHAO C Y, WEN M M. The role of RF, Ig, ANA and anti-ENA antibody in the diagnosis, treatment and prognosis of patients with rheumatoid arthritis[J]. Lab Med Clin, 2021, 18(23):3408-3411.
[7]	RAMOS-CASALS M, ROBERTO-PEREZ-ALVAREZ, DIAZ-LAGARES C, et al. Autoimmune diseases induced by biological agents: a double-edged sword?[J]. Autoimmun Rev, 2010, 9(3):188-193. doi: 10.1016/j.autrev.2009.10.003 URL
[8]	JANI M, DIXON W G, CHINOY H. Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far[J]. Rheumatology (Oxford), 2018, 57(11):1896-1907. doi: 10.1093/rheumatology/kex434 pmid: 29325166
[9]	YUKAWA N, FUJII T, KONDO-ISHIKAWA S, et al. Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to inflixi-mab in patients with rheumatoid arthritis: a retrospective clinical study[J]. Arthritis Res Ther, 2011, 13(6):R213.
[10]	刘卫霞, 庞爱梅, 郭绪晓, 等. 类风湿关节炎患者抗核抗体类型及相关抗体的研究[J]. 现代检验医学杂志, 2020, 35(1):65-66,70.
	LIU W X, PANG A M, GUO X X, et al. Research of antinuclear antibody pattern and the related antibody in patients with rheumatoid arthritis[J]. J Mod Lab Med, 2020, 35(1):65-66,70.
[11]	孙家祥, 李艳, 张乃丹, 等. 类风湿关节炎患者血清抗核抗体表达分析[J]. 实用检验医师杂志, 2019, 11(4):207-210.
	SUN J X, LI Y, ZHANG N D, et al. Analysis on expression of serum antinuclear antibody in patients with rheumatoid arthritis[J]. Chin J Clin Pathol, 2019, 11(4):207-210.
[12]	石青峰, 马韵, 杨峻, 等. 类风湿性关节炎患者抗核抗体及其多肽谱的检测[J]. 国际检验医学杂志, 2012, 33(23):2869-2870,2872.
	SHI Q F, MA Y, YANG J, et al. Detection and analysis of ANA and ANA profile in patients with rheumatoid arthritis[J]. Int J Lab Med, 2012, 33(23):2869-2870,2872.
[13]	KAVANAUGH A, TOMAR R, REVEILLE J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists[J]. Arch Pathol Lab Med, 2000, 124(1): 71-81. doi: 10.5858/2000-124-0071-GFCUOT pmid: 10629135
[14]	王家驷, 孙良丽, 焦鑫, 等. 抗核抗体及抗体谱在常见关节疾病中的临床表达特征分析[J]. 实用检验医师杂志, 2015(2):73-78.
	WANG J S, SUN L L, JIAO X, et al. Characteristic analysis of the clinical expressions of antinuclear antibody and antibody profiles in common joint diseases[J]. Chin J Clin Pathol, 2015(2):73-78.
[15]	CHELLINGWORTH M C, SALMON M, SCOTT D L, et al. The significance of IgM antinuclear antinuclear antibody in rheumatoid arthritis and other connective tissue diseases[J]. Rheumatol Int, 1984, 4(1):23-25. pmid: 6609412
[16]	尧荣凤, 陈小文, 许国祥. 类风湿关节炎患者IgG型与IgA型抗核抗体检测分析[J]. 中国骨与关节损伤杂志, 2019, 34(1):101-102.
	YAO R F, CHEN X W, XU G X. Analysis of IgG and IgA ANA tests in patients with rheumatoid arthritis[J]. Chin J Bone Joint Injury, 2019, 34(1):101-102.
[17]	ZHAI J, LIAO J, WANG M, et al. Anti-golgi antibody as a potential indicator for rheumatoid arthritis[J]. Lab Med, 2022, 53(2):156-160. doi: 10.1093/labmed/lmab046 URL
[18]	EMAD Y, RAGAB Y, HAMMAM N, et al. Autoantibo-dies to extractable nuclear antigens (ENAs) pattern in rheumatoid arthritis patients: Relevance and clinical implications[J]. Reumatol Clin (Engl Ed), 2021, 17(5):250-257.
[19]	KURAMOTO N, OHMURA K, IKARI K, et al. Anti-centromere antibody exhibits specific distribution levels among anti-nuclear antibodies and may characterize a distinct subset in rheumatoid arthritis[J]. Sci Rep, 2017, 7(1):6911. doi: 10.1038/s41598-017-07137-4 pmid: 28761166
[20]	廖永强, 彭可君, 夏洪娇, 等. 抗中性粒细胞胞浆抗体、抗核抗体联合检测对类风湿关节炎的诊断价值[J]. 现代生物医学进展, 2011, 11(13):2535-2537,2534.
	LIAO Y Q, PENG K J, XIA H J, et al. Diagnostic value of ANCA combing with ANA tests in patients with rheumatoid diseases[J]. Prog Mod Biomed, 2011, 11(13):2535-2537,2534.
[21]	ZHANG J F, YE X L, DUAN M, et al. Clinical and laboratory characteristics of rheumatoid arthritis with positive antinuclear antibody[J]. Beijing Da Xue Xue Bao Yi Xue Ban, 2020, 52(6):1023-1028.
[22]	PAKNIKAR S S, CROWSON C S, DAVIS J M, et al. Exploring the role of antinuclear antibody positivity in the diagnosis, treatment, and health outcomes of patients with rheumatoid arthritis[J]. ACR Open Rheumatol, 2021, 3(6):422-426. doi: 10.1002/acr2.11271 pmid: 34060254
[23]	孙志玲. 不同病程类风湿关节炎患者血清补体、抗核抗体、抗环瓜氨酸肽水平变化及临床意义探讨[J]. 临床研究, 2019, 27(4):152-153.
	SUN Z L. Changes and clinical significance of serum complement, ANA and CCP levels in patients with rheumatoid arthritis of different course[J]. Clin Res, 2019, 27(4):152-153.
[24]	李岚, 蔡枫, 茅婷婷, 等. 类风湿关节炎患者RF、ANA、CCP、Ig及炎症因子的水平测定及临床意义[J]. 现代生物医学进展, 2017, 17(30):5852,5912-5916.
	LI L, CAI F, MAO T T, et al. Determination and clinical significance of levels of RF, ANA, CCP, Ig and inflammatory factors in patients with rheumatoid arthritis[J]. Prog Mod Biomed, 2017, 17(30):5852,5912-5916.
[25]	裴文意, 蒋浩明, 袁海燕, 等. 老年类风湿性关节炎患者ANA和抗-CCP检测及其与抑郁的相关性[J]. 国际检验医学杂志, 2015, 36(20):2987-2988,2991.
	PEI W Y, JIANG H M, YUAN H Y, et al. ANA and anti-CCP detection in elderly patients with rheumatoid arthritis and their relationship with depression[J]. Int J Lab Med, 2015, 36(20):2987-2988,2991.
[26]	PUNZI L, DI-MAGGIO C, MAZZI A, et al. Lésions radiologiques des mains dans la polyarthrite rhumatoïde avec facteurs rhumatoïdes et anticorps antinucléaires [Radiological lesions of the hands in rheumatoid arthritis with rheumatoid factors and antinuclear antibodies][J]. Rev Rhum Mal Osteoartic, 1987, 54(7-9):563-566. pmid: 3499656
[27]	李亚波, 周芳, 邹映东, 等. 类风湿性关节炎合并核抗体阳性的临床意义[J]. 国际检验医学杂志, 2017, 38(2):184-186.
	LI Y B, ZHOU F, ZOU Y D, et al. The clinical significance of rheumatoid arthritis merger antinuclear antibody positive[J]. Int J Lab Med, 2017, 38(2):184-186.
[28]	KHATER E S, AL-SHEIK M F A. Clinical implications of autoantibodies to extractable nuclear antigens in rheumatoid arthritis patients in tertiary care hospital in Riyadh, Saudi Arabia[J]. Egypt J Immunol, 2022, 29(2):87-95. pmid: 35436058
[29]	DORMIDONTOV E N, OKHAPKINA O V, RIAZANTSEVA T A. The clinico-prognostic assessment of DNA antibodies and antinuclear factors in rheumatoid arthritis patients[J]. Ter Arkh, 1991, 63(8):96-99.
[30]	孙家祥, 李艳, 张乃丹, 等. RA患者抗核抗体阳性与贫血的关联性[J]. 甘肃医药, 2021, 40(4):310-312.
	SUN J X, LI Y, ZHANG N D, et al. Correlation between antinuclear antibody positive and anemia in RA patients[J]. Gansu Med J, 2021, 40(4):310-312.
[31]	王娟. 类风湿关节炎伴发干燥综合征患者临床及实验室特点分析[D]. 昆明医科大学, 2020.
	WANG J. Analysis of clinical and laboratory characteristics in patients with rheumatoid arthritis accompanied by Sjogren's syndrome[D]. Kunming Med Univ, 2020.
[32]	SOLOW E B, VONGPATANASIN W, SKAUG B, et al. Antinuclear antibodies are associated with all-cause mortality and cardiovascular outcomes in the general population[J]. J Am Coll Cardiol, 2015, 65(24):2669-2670. doi: S0735-1097(15)01920-8 pmid: 26088310
[33]	金静, 杜引会, 郑婕. ANA及IMT对老年类风湿关节炎患者并发颈动脉损害的预测价值及危险因素分析[J]. 解放军预防医学杂志, 2018, 36(6):736-737,741.
	JIN J, DU Y H, ZHENG J. Predictive value of ANA and IMT in elderly patients with rheumatoid arthritis complicated with carotid artery damage and risk factors[J]. J Prev Med Chin PLA, 2018, 36(6):736-737,741.
[34]	KRISTENSEN L E, DANESE S, YNDESTAD A, et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance[J]. Ann Rheum Dis, 2023, 82(7):901-910. doi: 10.1136/ard-2022-223715 pmid: 36931693
[35]	LUO L, LI X, YAN R, et al. Risk factors for adverse pregnancy outcomes in women with rheumatoid arthritis and follow-up of their offspring[J]. Clin Rheumatol, 2022, 41(10):3135-3141. doi: 10.1007/s10067-022-06233-9 pmid: 35698010
[36]	MORI A, SAITO T, TAKAHASHI M, et al. Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis[J]. PLoS One, 2020, 15(12):e0243729. doi: 10.1371/journal.pone.0243729 URL
[37]	LUPU A, TIERANU C, CONSTANTINESCU C L, et al. TNFα inhibitor induced lupus-like syndrome (TAILS) in a patient with IBD[J]. Curr Health Sci J, 2014, 40(4):285-288. doi: 10.12865/CHSJ.40.04.11 pmid: 26788358
[38]	HE Y, SAWALHA A H. Drug-induced lupus erythematosus: an update on drugs and mechanisms[J]. Curr Opin Rheumatol, 2018, 30(5):490-497. doi: 10.1097/BOR.0000000000000522 pmid: 29870500
[39]	WILLIAMS E L, GADOLA S, EDWARDS C J. Anti-TNF-induced lupus[J]. Rheumatology (Oxford), 2009, 48(7):716-720. doi: 10.1093/rheumatology/kep080 pmid: 19416947
[40]	TAKASE K, HORTON S C, GANESHA A, et al. What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort[J]. Ann Rheum Dis, 2014, 73(9):1695-1699. doi: 10.1136/annrheumdis-2014-205318 pmid: 24854356
[41]	ISHIKAWA Y, HASHIMOTO M, ITO H, et al. Anti-nuclear antibody development is associated with poor treatment response to biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis[J]. Semin Arthritis Rheum, 2019, 49(2):204-210. doi: 10.1016/j.semarthrit.2019.02.003 URL
[42]	BUCH M H, JOHNSEN A, SCHIFF M. Can switching to abatacept therapy in patients with rheumatoid arthritis on background methotrexate reverse TNF-inhibitor-induced antinuclear autoantibody/double-stranded DNA autoantibody conversion? An analysis of the AMPLE and ATTEST trials[J]. Clin Exp Rheumatol, 2019, 37(1):127-132. pmid: 30148437
[43]	ISHIKAWA Y, FUJII T, ISHIKAWA S K, et al. Immunogenicity and lupus-like autoantibody production can be linked to each other along with type Ⅰ Interferon production in patients with rheumatoid arthritis treated with infliximab: a retrospective study of a single center cohort[J]. PLoS One, 2016, 11(9):e0162896. doi: 10.1371/journal.pone.0162896 URL
[44]	BENUCCI M, SAVIOLA G, BAIARDI P, et al. Anti-nucleosome antibodies as prediction factor of development of autoantibodies during therapy with three different TNFalpha blocking agents in rheumatoid arthritis[J]. Clin Rheumatol, 2008, 27(1):91-95. doi: 10.1007/s10067-007-0728-5 pmid: 17929076
[45]	李娟娟, 高惠英. Toll样受体7介导免疫炎症与类风湿关节炎的发病机制[J]. 中国临床研究, 2022, 35(10):1435-1438.
	LI J J, GAO H Y. Toll-like receptor 7 in immune inflammation and the pathogenesis of rheumatoid arthritis[J]. Chin J Clin Res, 2022, 35(10):1435-1438.